Erectile insufficiency, to the extent that vaginal penetration is not possible, commonly referred to as "impotence," is thought to affect about 12% of adult men under age 45, about 20% of men at age 60, and about 55% of men at age 75.
A number of causes of erectile insufficiency, other than anatomical deficiencies of the penis or scrotum which preclude an erection sufficient for vaginal penetration, have been identified. Thus, in some males, the erectile dysfunction is psychological (due to, e.g., anxiety or depression) with no apparent somatic or organic impairment; such erectile dysfunction is referred to as "psychogenic." About 15%-20% of cases of impotence are psychogenic.
In other cases, the erectile dysfunction is associated with atherosclerosis of the arteries supplying blood to the penis; such dysfunction is referred to as "arteriogenic" or "atherosclerotic." About 40%-60% of cases of impotence are arteriogenic.
In still other cases, where the dysfunction is referred to as "venous leakage," or "abnormal drainage," there is leakage from veins in the penis such that sufficient pressure for an erection can be neither obtained nor maintained, particularly if, in addition, as commonly observed, there is also some arteriogenic dysfunction whereby supply of blood to the penis is impaired.
In still other cases, the dysfunction is associated with a neuropathy, or due to nerve damage arising from, e.g., surgery or a pelvic injury, in the nervous system affecting the penis; such a dysfunction is referred to as "neurogenic." About 10%-15% of cases of impotence are neurogenic.
Because of the high incidence of erectile insufficiency among diabetics, particularly those with insulin-dependent diabetes mellitus, erectile dysfunction in diabetics is often classified as "diabetogenic," although the underlying dysfunction is usually neurogenic associated with neuropathy but may be arteriogenic or both neurogenic and arteriogenic. About half of diabetic males suffer from erectile insufficiency, and about half of the cases of neurogenic impotence are in diabetics.
Further, erectile insufficiency is sometimes a side effect of certain drugs, such as beta-blockers, administered to reduce blood pressure in persons suffering from hypertension, or drugs to treat depression or anxiety. Excessive alcohol consumption has also been linked to erectile insufficiency. These forms of erectile insufficiency may be regarded as a subset of neurogenic or psychogenic insufficiency.
In any individual suffering from impotence, there may be more than one cause of erectile dysfunction.
A number of methods to cure or treat impotence are known. In cases of psychogenic dysfunction, psychological counseling is sometimes effective to cure the dysfunction. A case of psychogenic impotence often can be cured by counseling coupled with demonstrating to the patient that he is capable of having a full erection by inducing such an erection one or a few times in the patient.
Insufficiency due to excessive alcohol consumption is sometimes cured by reducing or eliminating such consumption.
In the rare cases where the insufficiency is untreatable on account of venous leakage, surgery can usually be employed to repair the venous lesion and thereby either cure the insufficiency or, if there remains an erectile insufficiency after repair of the venous lesion, render the insufficiency treatable by a pharmacological method, such as that of the present invention.
In some cases, particularly where the dysfunction is psychogenic or neurogenic and severe atherosclerosis is not involved, injection of papaverine, a smooth muscle relaxant, or phenoxybenzamine, a non-specific blocker and hypotensive, into a corpus cavernosum has been found to cause an erection sufficient for vaginal penetration. Papaverine is now widely used to treat impotence, although papaverine is ineffective in overcoming impotence due, at least in part, to severe atherosclerosis.
Also in cases where severe atherosclerosis is not a cause of the dysfunction, intracavernosal injection of phentolamine, an alpha-adrenergic blocker, causes an erection sufficient for vaginal penetration, but one of significantly shorter duration than one caused by intracavernosal injection of papaverine or phenoxybenzamine and of such short duration that satisfactory sexual relations are difficult or impossible.
Also widely used to treat impotence are penile implants, whereby an erection sufficient for vaginal penetration can be caused mechanically. In recent years, implants have been employed especially in cases where injections of papaverine are ineffective, which are usually cases of severe atherogenic impotence.
The neuropeptide, human vasoactive intestinal peptide (hereinafter referred to as "VIP"), is thought to be associated with erections in normal males (i.e., males not suffering from erectile insufficiency). Injection of up to 20 .mu.g of VIP (at 20 .mu.g/ml of diluent) into a corpus cavernosum of a normal male, without subjecting the male to sexual stimulation, causes only slight swelling (slight tumescence) of the penis but not an erection. However, when coupled with visual sexual stimulation, sexual stimulation by vibration, or both types of stimulation, as little as 1 .mu.g of the neuropeptide (at 1 .mu.g/ml of diluent) injected into a corpus cavernosum of a normal male facilitates full erection. See Wagner and Gerstenberg, World J. Urol. 5, 171-172 (1987). Prior to the present invention, doses of VIP that, on one hand, are adequate (when coupled with sexual stimulation) to induce erections in males suffering from impotence but that, on the other hand, minimize or avoid systemic side effects due to administration of VIP (such as flushing of the skin and hypotension) were not identified. It is known that VIP alone, coupled with sexual stimulation, does not induce erections in males who are impotent due to severe atherosclerosis.
The human neuropeptide, peptide N-terminal histidine C-terminal methionineamide (hereinafter referred to as "PHM"), has not, prior to the present invention, been identified as a substance that, together with sexual stimulation, is capable of inducing erections.
Treatment of impotence with papaverine or phenoxybenzamine often results in priapism, a locking-up of an erection for a long period of time, typically a few hours and sometimes longer than 24 hours. Priapism is a serious, deleterious side effect of treatment of erectile insufficiency with these drugs. Beyond the embarrassment that may be caused for some men, priapism is usually painful, irreversibly damages erectile tissue, and, to be relieved, requires bleeding or pharmacological intervention (e.g., injection of a sympathomimetic drug such as adrenaline). Even if priapism does not occur with use of papaverine, such use is associated with a painful, burning sensation in the first two or so minutes after the injection and there are indications that repeated use of papaverine causes undesirable, extensive intracavernous fibrosis. Further, as indicated above, impotence arising from severe atherosclerosis is not susceptible to treatment with papaverine, phenoxybenzamine, phentolamine or papaverine together with phentolamine.
In any case, phenoxybenzamine is not suitable for use in treating impotence because of the drug's carcinogenicity.
Treatment of impotence with penile implants also entails serious disadvantages. Such treatment requires surgery and entails total destruction of the erectile tissues of the penis, forever precluding normal erection.